2-phenylpyran-4-one derivatives

ABSTRACT

2-Phenylpyran-4-one derivatives of formula (I):  
                 
 
     wherein:  
     R 1  represents an alkyl or —NR 4 R 5  group, wherein R 4  and R 5  each independently represents a hydrogen atom or an alkyl group;  
     R 2  represents an alkyl, C 3 -C 7  cycloalkyl, pyridyl, thienyl, naphthyl, tetrahydronaphthyl or indanyl group, or a phenyl group which may be unsubstituted or substituted by one or more halogen atoms or alkyl, trifluoromethyl, hydroxy, alkoxy, methylthic, amino, mono- or dialkylamino, hydroxalkyl or hydroxycarbonyl groups;  
     R 3  represents a methyl, hydroxymethyl, alkoxymethyl, C 3 -C 7  cycloalkoxymethyl, benzyloxymethyl, hydroxycarbonyl, nitrile, trifluoromethyl or difluoromethyl group or a CH 2 —R 6  group wherein R 6  represents an alkyl group; and  
     X represents a single bond, an oxygen atom, a sulfur atom or a methylene group;  
     or pharmaceutically acceptable salts thereof, processes for their production and synthetic intermediates used in said processes, pharmaceutical compositions containing them and their use in medical treatment.

[0001] This invention relates to new therapeutically useful2-phenylpyran-4-one derivatives, to processes for their preparation andto pharmaceutical compositions containing them.

[0002] It is known that nonselective inhibition of the enzymecyclooxygenase (COX) prevents the overproduction of prostaglandinsassociated with inflammation, which are mediated by cyclooxygenase-2(COX-2) bu., at the same time, deprives tissues of basal levels ofprostaglandins necessary for the health of certain tissues mediatedlargely by cyclooxygenase-1 (COX-1). Non steroidal anti-inflammatorydrugs are non-selective inhibitors of COX and for that reason, have sideeffects of decreased renal blood flow, decreased platelet function,dyspepsia and gastric ulceration.

[0003] We have now found that certain 2-phenylpyran-4-one derivativesselectively inhibit COX-2 in preference to COX-1 and are useful in thetreatment of COX-2 mediated diseases, such as inflammation, pain, feverand asthma with fewer side effects.

[0004] Accordingly the present invention provides a 2-phenylpyran-4-onecompound of formula (I):

[0005] wherein

[0006] R¹ represents an alkyl or —NR⁴R⁵ group, wherein R⁴ and R⁵ eachindependently represents a hydrogen atom or an alkyl group;

[0007] R² represents an alkyl, C₃-C₇ cycloalkyl, pyridyl, thienyl,naphthyl, tetrahydronaphthyl or indanyl group, or a phenyl group whichmay be unsubstituted or substituted by one or more halogen atoms oralkyl, trifluoromethyl, hydroxy, alkoxy, methylthio, amino, mono- ordialkylamino, hydroxyalkyl or hydroxycarbonyl groups;

[0008] R² represents a methyl, hydroxymethyl, alkoxymethyl, C₃- C₇cycloalikoxymethyl, benzyloxymethyl, hydroxycarbonyl, nitrile,trifluoromethyl or difluoromethyl group or a CH₂-R⁶ group whereinR⁶represents an alkyl group; and

[0009] X represents a single bond, an oxygen atom, a sulfur atom or amethylene group;

[0010] or a pharmaceutically acceptable salt thereof.

[0011] The alkyl groups and moieties such as those present in thealkoxy, hydroxyalkyl, mono- or di-alkylamino groups, mentioned inrelation to the groups R¹ to R⁶ are usually “lower” alkyl that iscontaining from 1 to 6 particularly from 1 to 4 carbon atoms, thehydrocarbon chain being branched or straight. Preferred alkyl groups:,and where relevant alkyl moieties, include methyl, ethyl, propylincluding i-propyl, and butyl including n-butyl, t-butyl and sec-butyl.

[0012] In a phenyl group substituted by one or more halogen atoms oralkyl, trifluoroalkyl, hydroxy, alkoxy, methylthio, amino, mono- ordialkyl amino, hydroxyalkyl or hydroxycarbonyl groups, the phenyl ringmay be substituted by 1, 2, 3, 4 or 5 substituents, preferably 1, 2 or 3substituents, each being independently selected from the possiblesubstituents set out above. The phenyl group (attached to X or thepyran-4-one ring through its 1-position) may be substituted at any ofthe remaining positions, that is to say the 2, 3, 4, 5 or 6-positions. Aphenyl group having more than one substituent may be substituted at anycombination of positions. For example a phenyl group having twosubstituents may be substituted at the 2 and 3, 2 and 4, 2 and 5, 2 and6, 3 and 4 or 3 and 5 positions.

[0013] In particular, it is preferred that R² represents a branchedalkyl, C₃-C₇ (preferably C₃, C₅ or C₆) cycloalkyl, napthyl,tetrahydronaphthyl or indanyl group, an unsubstituted phenyl group or aphenyl group substituted by one or more halogen atoms, alkoxy groups,preferably methoxy groups, and/or alkyl groups, preferably methylgroups. The phenyl group preferably has 1, 2 or 3 substituents, morepreferably 1 or 2 substituents. Halogen atoms are preferably selectedfrom fluorine, chlorine and bromine atoms. When R² as a phenyl groupsubstituted by one or more halogen atoms, alkoxy groups and/or alkylgroups, preferably one of the substitutions is at the 4-position of thephenyl group. When R² Is a phenyl group substituted by one or twohalogen atoms at least one of the substitutions is preferably on the 2-or the 4-position.

[0014] It is preferred that R¹ independently represents an unsubstitutedalkyl croup such as methyl, ethyl, propyl or butyl, preferably methyl,or an NH₂ group (i.e. PR⁴ and R⁵ in the above formula both independentlyrepresent an H atom)

[0015] It is also preferred that R³ independently represents anunsubstituted alkyl group such as methyl, ethyl, propyl or butyl,preferably methyl, a nitrile group, a hydroxymethyl group, amethoxymethyl group, a difluoromethyl group or a hydroxycarbonyl group.

[0016] It is further preferred that X independently represents a singlebond, an oxygen atom or a methylene group more preferably a single bondor an oxygen atom.

[0017] Specific examples of the 2-phenylpyran-4-one derivatives of thepresent intention include:

[0018] 2-(4-methanesulfonylphenyl) -6-methyl-3-phenylpyran-4-one,

[0019]3-(4-fluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,

[0020]3-(3-fluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,

[0021]3-(2-fluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,

[0022]3-(4-chlorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,

[0023]3-(3-chlorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,

[0024]3-(2-chlorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,

[0025]3-(4-bromophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,

[0026] 2-(4-methanesulfonylphenyl)-6-methyl-3-p-tolylpyran-4-one,

[0027] 2-(4-methanesulfonylphenyl)-6-methyl-3-m-tolylpyran-4-one,

[0028] 2-(4-methanesulfonylphenyl)-6-methyl-3-to-tolylpyran-4-one,

[0029]2-(4-methanesulfonylphenyl)-6-methyl-3-(4-trifluoromethylphenyl)pyran-4-one,

[0030]3-(2,4-difluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,

[0031] 3-(3,4-difluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,

[0032]3-(3,5-difluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4- one,

[0033] 3-(2,5-difluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,

[0034]3-(2,6-difluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,

[0035]3-(2,4-dichlorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,

[0036] 3-(3,4-dichlorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,

[0037]3-(3-fluoro-4-methoxyplenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,

[0038]3-(4-chloro-3-fluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,

[0039]3-(2-chloro-4-fluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,

[0040] 3-(4-bromophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,

[0041]3-(4-fluorophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one

[0042]3-(2,4-difluorophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,3-cyclohexyl-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,

[0043] 2-(4-methanesulfonylyphenyl)-6-methyl-3-naphthalen-2-ylpyran-4-one,

[0044] 4-(6-methyl-4-oxo-3-phenyl-4H-pyran-2-yl) benzenesulfonamide,

[0045] 4-[3(4-fluorophenyl)-6-methyl-4-oxo-4H-pyran-2-yl]benzenesulfonamide,

[0046]4-[3-(3,4-dichlorophenyl)-6-methyl-4-oxo-4H-pyran-2-yl]benzenesulfonamide,

[0047]5-(2,4-difluorophenyl)-6-(4-methanesulfonylphenyl)-4-oxo-4-pyran-2-carbontrile

[0048]3-(2-fluorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one,

[0049]3-(4-chlorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one,

[0050]3-(2-chlorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one,

[0051]3-(2,5-difluorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one,

[0052]3-(3-chloro-4-methylphenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,

[0053] 2-(4-methanesulfonylphenyl)-6-methyl-3-phenoxypyran-4-one,

[0054]3-(4-fluorophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,

[0055] 2-(4-methanesulfonylphenyl)-6-methyl-3-(4-methylphenoxy)pyran-4-one,

[0056]3-(4-chlorophenyl)-2-(4-methanesulfonylphenyl)-methoxyphenylpyran-4-one,

[0057] 3-(4-chlorophenyl)-6-difluoromethyl-2-(4-methanesulfonyl-phenyl)pyran-4 -one,

[0058] and anyone of the compounds specifically identified in Table 4,and pharmaceutically acceptable salts thereof.

[0059] Of outstanding interest are:

[0060]3-(4-4fluorophenyl))-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,

[0061]3-(4-fluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,

[0062]3-(4-chlorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-3-(4-bromophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,

[0063]3-(2,4-difluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4 -one,

[0064]3-(3,4-dichlorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,

[0065]3-(3-chloro-4-methylplenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,

[0066] 2-(4-methanesulfonylphenyl)-6-methyl-3-phenoxypyran-4-one,

[0067] 3-(4-fluorophenoxy)-2-(4 -methanesulfonylphenyl)-6-methylpyran-4-one,

[0068]3-(2-fluorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one,

[0069] 3-(4-chlorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-5one,

[0070]3-(2-chlorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one,

[0071]3-(4-bromophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,

[0072] 2-(4-methanesulfonylphenyl)-6-methyl-3-(4-methylphenoxy)pyran-4-one,

[0073]3-3-2,4-difluorophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,

[0074] 3-(2,6-difluorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one,

[0075]2-(4-chlorophenyl)-2-(4-methanesulfonylphenyl)-6-methoxy-methylpyran-4-one,

[0076]3-(4-chlorophenyl)-6-difluoromethyl-2-(4-methanesulfonyl-phenylpyran.-4-one,

[0077] and pharmaceutically acceptable salts thereof.

[0078] The present invention also provides processes for preparing acompound of formula (I) which depend or the definition of R³. When R³ isa methyl group, compounds of formula (I) are prepared according to thedefinition of R¹. Thus, compounds of formula (I) in which R³ is a methylgroup and R¹ is an alkyl or —NR⁴R⁵ group in which R⁴ and R⁵ are alkylgroups, viz. a 2-phenylpyran-4-one derivative of formula (II)

[0079] wherein R^(1a) is an alkyl or —NR^(4a)R^(5a) group in which R⁴aand R^(5a) are each independently alkyl groups, and R² and X are asdefined above, which comprises reacting a carbonyl derivative of formula(III):

[0080] wherein R^(1a), R² and X are as defined above with an excess ofanhydrous acetic acid and polyphosphoric acid at a temperature from 100°C. to 150° C.

[0081] The carbonyl derivative of formula (III) may be obtained bymethods well known in the literature (E-A-7148831 WO96/068401WO96/31509an and DE-204520) or when X represents an oxygen or sulfuratom, by reacting a phenacyl derivative of formula (IV):

[0082] wherein R^(1a) is as defined above and Y represents a chlorine orbromine atom, with a hydroxy or mercapto derivative of formula (V):

HX^(a)—R²   (V)

[0083] wherein 2 is as defined above and X^(a) is an oxygen or sulfuratom.

[0084] The reaction between the phenacyl derivative of formula (IV) andthe intermediate compound of formula (V) may be carried out by heating amixture of these two starting materials, optionally in a solvent mixtureof methylene chloride, benzene or toluene and water, at a temperature offrom 15° C. to 30° C. and in the presence of a phase transfer catalystas benzyltriethylamonium chloride.

[0085] The carbonyl derivative of formula (III) in which X is other thana sulfur atom, may also be prepared by reacting a thio derivative offormula (VI):

[0086] wherein R^(1a) and R² are as defined above, and X^(b) is a singlebond, an oxygen atom or a methylene group, with an oxidizing agent,preferably magnesium monoperoxyphthalate or 3-chloroperoxybenzoic acid.The reaction is preferably carried out in an organic solvent such as amixture of methylene chloride with methanol or ethanol, at a temperatureof from 10° C. to 40° C.

[0087] The present invention also provides a process for the preparationof a compound of formula (I) wherein R³ is a methyl group, R¹ is analkyl group, and X is other than a sulfur atom viz. 2-phenylpyran-4-onederivative of formula (VII):

[0088] wherein R^(1b) is an alkyl group and R² and X^(b) are as definedabove by reacting a mercapto derivative of formula (VIII):

[0089] wherein R^(1b), R² and X^(b) are as defined above with anoxidizing agent, preferably with magnesium monoperoxyphthalate or3-chloroperoxybenzoic acid

[0090] The reaction between the mercapto derivative of formula (VIII)and the oxidizing agent is preferably carried out, as previouslydisclosed for the compound of formula (VI), in an organic solvent suchas a mixture of methylene chloride with methanol or ethanol, at atemperature of from 10° C. to 40° C.

[0091] The present invention additionally provides a process for thepreparation of a compound of formula (I) wherein R¹ is a —NR⁴R⁵ groupand R³ is a methyl group, viz. 2-phenylpyran-4-one derivative of formula(IX):

[0092] wherein R², R⁴, R³ and X are as defined above by reacting achlorosulfonyl derivative of formula (X):

[0093] wherein R² and X are as defined above with an amine of formula(XI):

R⁴—NH—R⁵   XI)

[0094] wherein R⁴ and R⁵ are as defined above.

[0095] This reaction is preferably carried out at a temperature Of from10° C. to 40° C.

[0096] The chlorosulfonyl derivative of formula (X) may, for example, beprepared by reacting a compound of formula (XII):

[0097] wherein R² and X are as defined above with chlorosulfonyl acid,preferably at a temperature of from 80° C. to 120° C.

[0098] The present invention further provides a process For thepreparation of a compound of formula (I) wherein R³ is a methyl groupand R¹ is a group wherein R⁴ and R⁵ are hydrogen, viz, the2-phenylpyran-4-one derivative of formula (XIII):

[0099] wherein R² and X are as defined above by debenzylation of thecorresponding N,N-dibenzyl derivative of formula (XIV):

[0100] wherein R² and X are as defined above.

[0101] The debenzylation is preferably carried out with an excess oftrifluoroacetic, sulfuric or methanesulfonic acid at a temperature offrom 0° C. to 120° C.

[0102] The intermediate of formula (XIV) may be prepared according tothe above processes using appropriate starting materials wherein R⁴ andR⁵ (or R^(4a) and R^(5a)) both represent benzyl groups.

[0103] The intermediate of formula (IV) and (VI) used in the preparationof the compounds of the invention may be prepared by methods disclosedin the literature, for example, in M. F. Saettone, J. Org. Chem. 31, p1959 (1966) and WO-9606840.

[0104] The intermediate compounds of formulae (VIII) and (XII) may beprepared by the same process disclosed for the preparation of compoundsof formula (II), with the appropriate starting materials.

[0105] The 2-phenylpyran-4-ore derivatives of formula (I) wherein R³ isother than a methyl group, can be prepared by processes which arerepresented in the following scheme:

[0106] As can be seen in the scheme, 2-phenylpyran-4-one derivatives offormula (I) wherein R³ is other than a methyl group, viz. compounds offormulae (XVII), (XVIII), (XIX), (XX), (XXI), (XXII) and (XXIV), areprepared from compounds of formula (I) in which R³ is a methyl group,viz. compound of formula (XV), which processes of preparation have beendisclosed above. In a first stage, compounds of formula (XV) are treatedwith an oxidizing agent as selenium dioxide in an organic solvent astetrahydrofuran or dioxan, in a pressure vessel and at a temperaturefrom 100° C. to 190° C. The corresponding aldehyde of formula (XVI) isobtained, which is used as starting material to obtain the compounds offormula (Z) with R³ other than a methyl croup.

[0107] The compounds of Formula (I) wherein R³ is a hydroxycarbonylgroup, viz. compound of formula (XVII), are prepared from thecorresponding aldehyde (XVI) by reaction with an oxidizing agent aspyridinum dichromate or manganese dioxide in an organic solvent asN,N-dimethylformamide or ethanol at a temperature between −5° C. and 35°C. The obtained compounds (XVII are used as starting materials to obtaincompounds of Formula (I) wherein R² is a trifluoromethyl group, viz.compound of formula (XVIII). Ate reaction Is carried out by reaction ofcompounds (XVII) with a mixture of sulphur tetrafluoride rand hydrogenfluoride, optionally in the presence of an organic solvent as methylenechloride, in a pressure vessel, and at a temperature from 20° C. to 140°C.

[0108] The compounds of formula (I) wherein R³ represents ahydroxymethyl group viz. compounds of formula (XIX) are prepared byreduction of compounds (XVI) with a boron or aluminium hydride,preferably sodium borohydride in a solvent as methanol or ethanol and ata temperature from 10° C. to 40° C. Further reaction of compounds (XIX)with an appropriate halide of formula (XXIII):

Z—R⁷   (XXIII)

[0109] wherein Z represents a chlorine, bromine or iodine atom and R⁷represents an alkyl, C₃-C₇ cycloalkyl or benzyl group, provide thecompounds of formula (I) wherein R³ is an alkoxymethyl, C₃-C₇cycloalkoxymethyl or benzyloxymethyl group viz. compounds of formula(XX). The reaction is carried out in an organic solvent such as acetone,N,N-dimethylformamide or tetrahydrofuran in the presence of sodium orpotassium hydride or amide, and at a temperature between 20° C. and 120°C.

[0110] Also aldehydes of formula (XVI) are used as starting material toobtain compounds of formula (I) wherein R³ is a nitrile group, viz.compounds of formula (XX:). The reaction is carried out n a first stageby treatment of aldehydes (XVI) with hydroxylamine hydrochloride andformic acid at a temperature from 80° C. to 120° C. The resulting oximederivative is isolated and heated with an excess of acetic anhydride ata temperature between 100° C. to 180° C.

[0111] The compounds of formula (I) wherein R³ represents adifluoromethyl group, viz. compounds of formula (XXII), are preparedfrom aldehydes of formula (XV:) by reaction with a fluorinated reagentas diethylaminosulfur trifluoride, or a mixture of sulfurtetrafluoride-hydrogen fluoride, optionally in the presence of anorganic solvent as methylene chloride, benzene or toluene and at atemperature from 0° C. to 130° C.

[0112] The 2-phenylpyran-4-one derivatives of formula (I) in which R³ isa CH₂—R⁶ croup, viz. compounds of formula (XXIV), are also prepared fromaldehydes of formula (XVI) in a two stages process. In the first stage,the aldehyde (XV:) is reacted with a triphenylphosphine derivative (XXV)in the presence of a solvent as dioxane, dimethoxyethane ortetrahydrofuran at a temperature from 15 to the boiling point of thesolvent. The resulting compound is hydrogenated in the second stage ofthe process in the presence of a catalyst as palladium or activatedcarbon. The reaction is carried out in the presence of a solvent asmethanol, ethanol or ethyl acetate at a temperature from 15° C. to 40°C.

[0113] The 2-phenylpyran-4-one derivatives of formula (I) in which thereis the presence of a basic group, can be converted by methods know perse into pharmaceutically acceptable salts, preferably acid additionsalts by treatment with organic or inorganic acids as fumaric, tartaric,succinic or hydrochloric acid. Also, 2-phenylpyran-4-one derivatives offormula (I) in which R³ represents an hydroxycarbonyl group, may beconverted into pharmacologically acceptable salts with, for instance,alkali metals such as sodium or potassium by reaction with an alkalimetal hydroxide.

[0114] The following biological tests and data further illustrate thisinvention.

[0115] COX-1 and COX-2 activities in human whole blood

[0116] Fresh blood from healthy volunteers who had not taken anynon-steroidal ante-inflammatory drugs for at least 7 days prior to bloodextraction was collected in heparinized tubes (20 units of heparin perml) or the COX-1 activity determination, 500 μl aliquots of blood wereincubated with either 5 μl vehicle (dimethylsulphoxide) or 5 μl of atest compound for 1 h at 37° C. Calcium ionophore A23187 (25 μM) wasadded 20 min before stopping the incubation. Plasma was separated bycentrifugation (10 min at 13000 rpm) and kept at −30° C. until TXB₂levels were measured using an enzyme immunoassay kit (ELISA). The effectof the compounds were evaluated by incubating each compound at five tosix different concentrations with triplicate determinations. IC₅₀ valueswere obtained by non-linear regression using InPlot, GraphPad softwareon an IBM computer.

[0117] For the COX-2 activity determination, 500 μl aliquots of bloodwere incubated in the presence of LPS (10 μg/ml) for 24 h at 37° C. inorder to induce The CCX-2 expression (Patriagnani et al., J. Pharm.Exper. Ther. 271; 1705-1712 (1994)), Plasma was separated bycentrifugation (10 min at 13000 rpm.) and kept at −30° C. until PGE₂levels were measured using an enzyme immunoassay kit (ELISA). Theeffects of inhibitors were studied by incubating each compound (5 μlaliquots) at five to six different concentrations with triplicatedeterminations in the presence of LPS for 24 hours. IC₅₀ values wereobtained by non-linear regression using InPlot, GraphPad software on anIBM computer.

[0118] Anti-inflammatory activity (adjuvant arthritis)

[0119] Male Wistar rats weighing 175-200 g with free access to food andwater were used. On day 0, the animals received an intraplantarinjection of a suspension of Mycobacterium tuberculosis in paraffin oil(0.5 mg/rat) on the left hind paw. A group of nonarthritic control ratswere injected with paraffin oil alone. On days 11 and 14 after inductionof arthritis, the volume of the hind paw of each rat was measured usinga water plethysmograph. Animals whose paw volumes increased during thattime were selected. Rats were distributed into groups of 8 having equalmean paw volumes and an approximately equal standard deviation

[0120] Test compounds were administered p.o. once daily for 7 days (days14-20). Nonarthritic and arthritic control rats received vehicle alonefor 7 days. The hind paw volumes were measured 20 h after the last dose(on day 21). The body weight was determined every second day.

[0121] The results were expressed as the percentage of inhibition ofinflammation (paw volume) for each treatment group, considering both thearthritic and nonarthritic vehicle controls. The ANOVA tests was usedfor statistical studies.

[0122] Ulcerogenic activity

[0123] Animals: Male Wistar rate (Interfauna, U.K., Ltd) weighing about150-175 g were used. Animals were maintained on a 12:12 hour light-darkcycle (lights on at 7:00 am) at room temperature (22±1° C.). Food andwater were allowed ad libitum.

[0124] Procedure: The compounds were administered by the oral route oncea day for 4 consecutive days. The body weight of each rat was assessedevery day before drug administration. The animals were anesthesized 24 hafter the last dosing and 1 ml of blood was extracted by cardiacpuncture using heparin (10 U/ml) as anticoagulant. The percentage ofhematocrit was measured. The intestines were removed, openedlongitudinally and gently washed. The macroscopic severity of theintestinal erosions was assessed using a parametric scale, evaluatingthe number of the perforated and non-perforated intestinal ulcers bymeans of a lesion index ranging from 0 to 3 (0:no ulcers, 1:<10 ulcers,2:10-25 ulcers to 3:>25 ulcers). No gastric ulcers are observed usingthis protocol.

[0125] The treatments were randomized in each experiment. The resultswere compared with those obtained in the vehicle-treated group using theANOVA test.

[0126] Results

[0127] The results obtained from the biological assays are shown inTable 1, 2 and 3. TABLE 1 COX-1 and COX-2 Inhibition COX-1 COX-2Compound (*) IC₅₀ (μM) IC₅₀ (μM) Ratio COX-1/COX-2 Indomethacin 0.190.22 0.86  2 >100 1.06 >94  4 >100 1.5 >66  5 >100 2.1 >47  8 >1001.7 >58 15 100 1.1 90 22 37.1 0.7 53 31 >100 1.67 >59 37 >100 1.08 >9239 >100 0.96 >104 40 27 0.14 193 41 >100 0.35 >285 42 41 0.2 205 43 >1000.8 125 44 39 0.21 185 45 22 0.15 147 47 57.1 0.8 71 63 44 1.73 2567 >100 2.1 >47

[0128] TABLE 2 Anti-inflammatory activity % Inhibition Compound (dose,mg/kg) Indomethacin 64 (1)  5 50 (1) 22 69 (1) 39 75 (1) 41 71 (1 45 74(1)

[0129] TABLE 3 Ulcerogenic activity Lesion index Compound Dose (mg/kg)PU NPU Hematocrit (%) Vehicle 0 0 44.3 ± 0.2 Tridomethacin  10 3 3 22.7± 1.6  5 100 0 0 44.1 ± 0.7 22 100 0 0 44.4 ± 0.3 39 100 0 0 43.7 ± 0.441 100 0 0 43.4 ± 1.9 45 100 0 0 44.4 ± 0.9

[0130] As shown in Table 1, the 2-phenylpyran-4-ore derivatives offormula (I) are potent and selective CCX-2 inhibitors whereas thereference compound indomethacin is as equipotent as COX-2 and COX-1inhibitor. Due to their low COX-1 inhibitory activity, the compounds offormula (I) present an important anti-inflammatory activity (see Table2) and the benefit of significantly less harmful side effects than thenon-steroidal anti-inflammatory drugs commonly used (e.g.gastrointestinal toxicity (see Table 3), renal side-effects, reducedeffect on bleeding times and asthma induction in aspirin-sensitivesubjects).

[0131] Thus the compounds of the invention are preferably selectiveinhibitors of mammalian COX-2, for example human COX-2. the compounds ofthe invention also preferably have low inhibitory activity towardmammalian COX-1, for example human COX-1. Inhibitory activity cantypically be measured by in vitro assays, or example as described above.

[0132] Preferred compounds of the invention have an IC₅₀ value for COX-2of less than 5 μm, preferably less than 3 more preferably less than 2.5μm. Preferred compounds of the invention also have an IC₅₀ value forCOX-1 of greater than 10 μM, preferably greater than 20 μM. As anindicator of selectivity for inhibition of COX-2 over COX-1, the ratioof COX-1/COX-2 IC₅₀ values is preferably greater than 20, 30 or 50, morepreferably greater than 80, 90 or 100.

[0133] The present invention further provides a compound of formula (I)for use in a method of treatment of the human or animal body by therapy,in particular for the treatment of pain, fever or inflammation, toinhibit prostanoid-induced smooth muscle contraction or for theprevention of colorectal cancer or neurodegenerative diseases.

[0134] The present invention further provides the use of a compound offormula (I) in the manufacture of a medicament for the treatment ofpain,, fever or inflammation, to inhibit prostanoid-induced smoothmuscle contraction or for the prevent-ion of colorectal cancer orneurodegenerative diseases.

[0135] The compounds of formula (I) are useful for relief of pain, feverand inflammation of a variety of conditions including rheumatic fever,symptoms associated with influenza or other Spiral infections, commoncold, low back and neck pain, dysmenorrhoea, headache, toothache,sprains and strains, myositis, neuralgia, synovitis, bursitis,tendinitis, injuries, is following surgical and dental procedures andarthritis including rheumatoid arthritis, osteoarthritis, goutyarthritis, spondyloarthopathies, systemic lupus erythematosus andjuvenile arthritis and bone resorption. They may also be used in thetreatment of skin inflammation disorders such as psoriasis, eczema,burning and dermatitis. In addition, such compounds may be used for theprevention of colorectal cancer.

[0136] The compounds of formula (I) well also inhibit prostanoid-inducedsmooth muscle contraction and therefore may be used in the treatment ofdysmenorrhoea, premature labour, asthma and bronchitis.

[0137] The compounds of formula (I) can be used as alternative toconventional non-steroidal anti-inflammatory drugs, particularly wheresuch non-steroidal anti-inflammatory drugs way be contraindicated suchas the treatment of patients with gastrointestinal disorders includingpeptic ulcers, gastritis, regional enteritis, ulcerative colitis,diverticulitis, Crohn's disease, inflammatory bowel syndrome andirritable bowl syndrome, gastrointestinal bleeding and coagulationdisorders, kidney disease (e.g. impaired renal function), those prior tosurgery or taking anticoagulants, and those susceptible to non-steroidalanti-inflammatory drugs induced asthma.

[0138] The compounds can further be used to treat inflammation indiseases such as vascular diseases, migraine headaches, periarteritisnodosa, thyroiditis, aplastic anaemia, Hodgkin's disease, scleroderma,type I diabetes, myasthenia gravis, sarcoidosis, nephrotic syndrome,Behcet's syndrome, polymyositis, hypersensitivity, conjunctivitis,gingivitis, myocardial ischaemia and stroke.

[0139] Compounds of the present invention are inhibitors ofcyclooxygenase-2 enzyme and are thereby useful to treat thecyclooxygenase-2 mediated diseases enumerated above. These compounds canfurther be used for the prevent on of neurodegenerative diseases such asAlzheimer's disease.

[0140] Accordingly, the 2-phenylpyran-4-one derivatives of formula (I)and pharmaceutically acceptable salts thereof, and pharmaceuticalcompositions comprising such compounds and/or salts thereof, may be usedin a method of treatment ova disorders of the human body which comprisesadministering to a patient requiring such treatment an effective amountof a 2-phenylpyran-4-one derivative of formula () or a pharmaceuticallyacceptable salt thereof.

[0141] The present invention also provides pharmaceutical compositionswhich comprise, as an active ingredient, as least a 2-phenylpyran-4-onederivative of formula (I) or a pharmacologically acceptable salt thereofin association with a pharmaceutically acceptable excipient such as acarrier or diluent. The active ingredient may comprise 0.001% to 99% byweight, preferably 0.01 to 90% by weight of the composition dependingupon the nature of the formulation and whether further dilution is to bemade prior to application.

[0142] Preferably the compositions are made up in a form suitable fororal, topical, nasal, inhalation, rectal, percutaneous or injectableadministration.

[0143] The pharmaceutically acceptable excipients which are admixed withthe active compound, or salts of such compound, to form the compositionsof this invention are well-known per se and the actual excipients useddepend inter alia on the intended method of administering thecompositions.

[0144] Compositions so this invention are preferably adapted forinjectable and per os administration. In this case, the compositions fororal administration may take the form of tablets, retard tablets,sublingual tablets, capsules or liquid preparations, such as mixtures,elixirs, syrups or suspensions, all containing the compound of theinvention; such preparations may be made by methods well-known in theart.

[0145] The diluents which may be used in the preparation of thecompositions include those liquid and solid diluents which arecompatible with the active ingredient, together with colouring orflavouring agents, if desired. Tablets or capsules may convenientlycontain between 2 and 500 mg of active ingredient or the equivalentamount of a salt thereof.

[0146] The liquid composition adapted for oral use may be in the form ofsolutions or suspensions. The solutions may be aqueous lid solutions ofa soluble salt or other derivative of the active compound in associationwith, for example, sucrose to form a syrup. The suspensions may comprisean insoluble active compound of the invention or a, pharmaceuticallyacceptable salt thereof in association with water, together with asuspending agent or flavouring agent.

[0147] Compositions for parenteral injection may be prepared fromsoluble salts, which may or may not be freeze-dried and which may bedissolved in pyrogen free aqueous media or other appropriate parenteralinjection fluid.

[0148] Effective doses are normally in the range of 10-600 mg of activeingredient per day. Daily dosage may be administered in one or moretreatments, preferably from I to 4 treatments, per day.

[0149] The invention is illustrated by the following Examples, which donot limit the scope of the invention in any way.

EXAMPLE 1

[0150] a) To a solution of2-(4-fluorophenyl)-1-(4-methanesulfonylphenyl)ethanone (1 g; 3.4 moles)in glacial acetic acid (15 ml), polyphosphoric acid (10 g) was added andthen heated at 140° C. for 16 hours. After cooling, the reaction waspoured into ice-water, extracted with ethyl acetate (2×50 ml), theorganic solution dried (Na₂SO₄) and the solvent- removed under reducedpressure. The residual oil was purified by column chromatography withsilica gel and ethyl acetate as eluent3-(4-fluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one wasobtained (0.5 g) m.p. 237° C. (Compound 2 in Table 4).

EXAMPLE 2

[0151] a) To a solution of 2,4-difluorophenyl (3.71 g; 29 mmol) and2-bromo-1-(4-methylsulfonylphenyl)ethanone (7.00 g; 29 mmol) inmethylene chloride. (50 ml) was added a solution of potassium carbonate(5.91 g; 43 mmol) and tetrabutylammonium hydrogensulfate (0.48 g; 1.4mmol) in water (20 ml) The mixture was stirred at room temperature for1-6 hours. Water (100 ml) was added, the organic phase was decanted, andthe basic phase was extracted with methylene chloride (2×100 ml) Theorganic solution was dried (Na₂SO₄) and the solvent removed underreduced pressure. The resulting solid was washed with ethyl ether.2-(2,4-Difluorophenoxy)-1-(4-methylsulfanyl-phenyl)ethanone was obtained(6.6 g), m.p. 70-71° C.

[0152] b) To a solution of2-(2,4-difluorophenoxy)-1-(4-methylsulfonyl)ethanone (6.60 g; 22 mmol)in methylene chloride (100 ml), water (20 ml) and 80% magnesiummonoperoxyphatlate hexahydrate (15.26 g; 25 mmol) were added. Themixture was stirred at room temperature for 6 hours. The reaction waspoured into saturated solution of sodium bicarbonate (200 ml) andextracted with methylene chloride (3×100 ml). The organic phase wasdried (Na₂SO₄) and the solvent removed under reduced pressure. 2-(24-Difluorophenoxy)-1-(4-methanesulfonylphenyl)ethanone was obtained(4.97 g) as a solid, m.p. 161-163° C.

[0153] c) To a solution of2-(2,4-Difluorophenoxy)-1-(4-methanesulfonylphenyl)ethanone ( 4.60 g; 14mmol) in acetic acid (70 ml), polyphosphoric acid (45 g) was added andthen heated at 140° C. for 5 hours. After cooling, the reaction waspoured into ice-water, extracted with ethyl acetate (2×100 ml), theorganic solution dried (Na₂SO₄) and the solvent removed under reducedpressure. :he residual oil was purified by column chromatography withsilica gel and ethyl acetate/n-hexane (1:2) as eluent. Recrystallizationfrom ethanol gave3-(2,4-difluorophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one(0.64 g), m.p. 191° C. (Compound 45 in Table 4)-5

EXAMPLE 3

[0154] a) A solution of 4-(dibenzylsulfamoyl)benzoic acid (24 g; 63mmoles) in thionyl chloride (50 ml) was boiled under reflux for 2.5hours and the excess of thionyl chloride removed under reduced pressure.4-(dibenzylsulfamoyl)berzoyl chloride (25 g) was obtained as an oilwhich was used in the next step without purification.

[0155] b) To a solution of N,O-dimethylhydroxylamine hydrochloride (7.37g; 75.6 mmoles) and triethylamine (21.8 ml; 151 mmoles) in methylenechloride (150 ml), another solution of 4-(dibenzylsulfamoyl)benzoylchloride (25 g) in methylene chloride (150 ml) was slowly added and theresulting mixture stirred at room temperature for 16 hours. The solidwas filtered off, the solvent removed under reduced pressure and theresidual oil purified by column chromatography with silica gel andn-hexane-ethyl acetate 1.1 as eluent. N,O-dimethylamide of4-(dibenzylsulfamoyl)benzoic acid (22 g) was obtained, m.p.

[0156] c) To a suspension of magnesium (2 g; 82.4 mmoles) in anhydroustetrahydrofuran (20 ml), another solution of benzyl chloride (10.4 g;82.4 mmoles) in anhydrous tetrahydrofuran (130 ml) was slowly added.When the reaction was completed, a solution of N,(0-dimethylamide of4-(dibenzylsulfamoyl)benzoic acid () g, 16 5 mmoles) in anhydroustetrahydrofuran (50 ml) 30 was slowly added while the temperature wasmaintained at 0° C. After stirring at the same temperature for half anhour, the reaction mixture was poured into an ammonium chloridesaturated solution (100 ml), extracted with ethyl ether (3×75 ml) andthe organic extracts dried (Na₂SO₄). The solvent was removed underreduced pressure an the residual oil was purified by columnchromatography with silica gel and n-hexane-ethyl acetate 1:3 as eluent.N,N-dibenzyl-4-phenylacetylbenzesulfonamide (9.4 g) was obtained, m.p143° C.

[0157] d) To a solution of the above compound obtained in c) (9.4 g;20.7 mmoles) in glacial acetic acid (140 ml), polyphosphoric acid (94 g)was added and the resulting mixture heated to 140° C. for 16 hours.After cooling, the reaction mixture was poured into ice-water, extractedwith ethyl acetate (3×150 ml) and the organic solution dried (Na₂SO₄).The solvent was removed in vacuo and to the residual oil, concentratedsulfuric acid (38 ml) was added, then stirred at 0° C. for 10 minutes,further 60 minutes at room temperature and poured into ice-water. Theprecipitated solid was collected by filtration and purified by columnchromatography with silica gel and ethyl acetate as eluent.4-(6-methyl-4-oxo-3-phenyl-4H-pyran-2-yl)benzenesulfonamide (1.5 g) wasobtained, m.p. 218° C. (compound 54 in Table 4)

EXAMPLE 4

[0158] a) To a solution of 3,4-dichlorophenylacetophenone (5 3 g; 20mmoles) in glacial acetic acid (90 ml), polyphosphoric acid (64 g) wasadded and the resulting solution heated at 140° C. or 24 hours. Aftercooling, the reaction mixture was poured into ice-water, extracted withethyl acetate (3×75 ml), the organic solution dried (Na₂SO₄) and thesolvent removed under reduced pressure. The obtained residue waspurified by column chromatography with silica gel and n-hexane-ethylacetate 3:2 as eluent. 3-(3,4-dichlorophenyl)-2-phenyl-5methylpyran-4-one (1.68 g) was obtained, m.p. 104° C.

[0159] b) A solution of the compound obtained above (1.4 g; 4.3 mmoles)in chlorosulfonic acid (12 ml) was heated at 70° C. for 1.5 hours andafter cooling, the reaction mixture was slowly poured into ice-water andextracted with ethyl acetate (2×50 ml). The organic solution was dried(Na₂SO₄), the solvent removed under reduced pressure and to the residualoil, previously solved in methanol (10 ml), a saturated solution ofammoniac in methanol (40 ml) was slowly added. After stirring at roomtemperature for 1 hour, the solvent was removed under reduced pressure,the residue solved in ethyl acetate (100 ml) and the resulting solutionwas washed with water (2×100 ml), dried (Na₂SO₄) and the solvent removedunder reduced pressure. The residual oil was purified by columnchromatography wish silica gel and n-hexane-ethyl acetate 1:1 as eluent.4-[3-(3,4-dichlorophenyl)-6-methyl-4-oxo-4H-pyran-2-yl]benzenesulfonamide(0.5 g) was obtained, m.p. 128° C. (Compound 56 in Table 4).

EXAMPLE 5

[0160] a) To a solution of N,N-dibenzyl-4-(2-10bromoacetyl)benzenesulfonamide (10.5 g, 23 mmoles), and p-chlorophenol(2.94 g, 23 mmoles) in methylene chloride (42 ml), potassium carbonate(4.83 g, 34.7 mmoles) and tetrabutylammonium bromide (0.42 g, 1-2mmoles) in water (140 ml)was added. The reaction mixture was refluxedfor 16 hours. After cooling, the mixture was diluted with methylenechloride (150 ml). The organic layer was separated, washed with water,and dried (Na₂SO₄) The solvent was removed under reduced pressure.N,N-dibenzyl-4-[2-(4-chlorophenoxy)acetyl]benzenesulfonamide (11.7 g)was obtained as a semisolid residue, which was used in the next stepwithout further purification.

[0161] b) To a solution ofN,N-dibenzyl-4-[2-(4-chlorophenoxy)acetyl]benzenesulfonamide (11.7 g, 23mmoles) in acetic acid(105 ml), polyphosphoric acid (75 g) was added andthe resulting solution was heated at 140° C. for 5 hours. After cooling,the reaction mixture was poured into ice-water, extracted with ethylacetate (3×150 ml), and the organic solution was dried (Na₂SO₄). Thesolvent was removed under reduced pressure and the resulting oil wassolved in H₂SO₄ (33 ml) The mixture was stirred at room temperature for15 minutes, and poured into ice-water. The solid was filtered off andpurified by column chromatography silica gel and ethyl acetate/methylenechloride/acetic acid (78:10:1) as eluent.4-[3-(4-chlorophenoxy)-6-methyl-4-oxo-4H-pyran-2-yl]benzenesulfonamide(0.28 g) was obtained. m.p. 221° C. (Compound 57 in Table 4).

EXAMPLE 6

[0162] a) To a solution of3-(2,4-difluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one(1.7 g; 4.5 moles) (compound 13) in dioxane (45 ml), selenium dioxide(4.2 g, 20 mmoles) was added and the mixture heated in a pressure vesselat 180° C. for 1 hour. After cooling, the reaction mixture was filtered,the solvent removed under reduced pressure and the residual oil purifiedby column chromatography with silica gel and ethyl acetate as eluent.5-(2,4difluorophenyl)-6-(4-methanesulfonylphenyl)-4-oxo-4H-pyran-2-carbaldehyde(0.85 g) was obtained.

[0163] b) To a solution of the above compound (0.8 g; 2.1 mmoles) informic acid (6 ml), hydroxylamine hydrochloride (0.17 g; 2.7 mmoles) wasadded and the mixture heated at 100° C. for 2 hours. After cooling, thereaction mixture was poured into ice, 2N sodium hydroxide was addeduntil pH=7 and extracted with ethyl acetate (2×50 ml. The organicsolution was dried (Na₂SO₄) the solvent removed in vacuo and the residuewas dissolved in acetic anhydride (15 ml) and heated at 150° C. for 3hours. The solvent was removed under reduced pressure, the residuetreated with methylene chloride (50 ml) and the resulting solutionwashed with 2N sodium hydroxide (2×25 ml. The organic solution was dried(Na₂SO₄), the solvent removed in vacuo and the residue purified bycolumn chromatography with silica gel and n-hexane-ethyl acetate 1:1 aseluent.5-(2,4-difluorophenyl)-6-(4-methanesulfonylphenyl)-4-oxo-4H-pyran-2-carbontrile(0.2 g), m.p. 113° C. (Compound 59 in Table 4).

EXAMPLE 7

[0164] a) To a solution of3-(4-chlorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one (4.0g, 10.6 mmoles) in dioxane (50 ml), selenium dioxide (5.9 g, 53 mmoles)was added and heated into a sealed tube at 180° C. for 30 minutes. Aftercooling, the raw material was filtered through Celite and the solventwas removed under reduced pressure. The resulting oil was purified bycolumn chromatography with silica gel and ethyl acetate/n-hexane (2:1)as eluent.S-(4-chlorophenyl)-6-(4-methanesulfonylphenyl)-4-oxo-4-pyran-2-carbaldehyde(1.80 g) was obtained.

[0165] b) To a solution of5-(4-chlorophenyl)-6-(4-methanesulfonylphenyl)-4-oxo-4H-pyran-2-carbaldehyde(1 8 g, 4.6 mmoles) in methanol (30 ml), sodium borohydride (0.26 g, 6.9mmoles)was slowly added at 0° C. The resulting mixture was stirred for30 minutes at room temperature. The reaction mixture was concentratedand the residue was solved in ethyl acetate. The organic layer waswashed with water, dried (Na₂SO₄), and the solvent was removed underreduced pressure. The resulting residue was purified by columnchromatography with silica gel and ethyl acetate/n-hexane (1:1) aseluent.3-4A-chlorophenyl)-6-hydroxymethyl-2-(4-methanesulfonylphenyl)pyran-4-one(0.9 g) was obtained. m.p. 120° C. (Compound 60 in Table 4).

EXAMPLE 8

[0166] a) To a solution of3-(4-chlorophenyl)-6-hydroxymethyl-2-(,4-methanesulfonylphenyl)pyran-4-one(0.5 g, 1.3 mmoles) in methylene chloride (10 ml), methyl iodide (0.24ml, 3.86 mmoles), and a solution of sodium hydroxide (0.41 g, 10.3mmoles) and tetrabutylammonium chloride (50 ml) in water (0.8 ml) wereadded. The reaction mixture was stirred at room temperature for 18hours. The organic layer was diluted with methylene chloride (20 ml),washed with water and dried (Na₂SO₄). The solvent was removed underreduced pressure. The resulting solid was purified by columnchromatography with silica gel and ethyl acetate as eluent.3-(4-chlorophenyl)-2-(4-methanesulfonylyphenyl)-6-methoxyphenylpyran-4-one(0.15 g) was obtained. m.p. 162° C. (Compound 63 in Table 4)

EXAMPLE 9

[0167] a) To a solution of silver nitrate (0.88 g, 5.1 mmoles) in water(4 ml), a solution of sodium hydroxide (0.42 g, 6.2 mmoles) in water (4ml) was added. The reaction mixture was stirred for 15 minutes at roomtemperature, and a solution5-(4-chlorophenyl)-6-(4-methanesulfonylphenyl-4-one-4H-pyran-2-carbaldehydein tetrahydrofuran (10 ml) was added. The reaction mixture was stirredfor 3 hours at room temperature and filtered through Celite. The solventwas removed under reduced pressure and the residue was solved in ethylacetate. The organic layer was washed with water and dried (1Na₂SO₄).The solvent was removed under reduced pressure. The resulting solid waspurified by column chromatography with silica gel and ethylacetate/methylene chloride/acetic acid (78:10:1) as eluent.5-(4-chlorophenyl)-6-(4-methanesulfonylphenyl)-4-oxo-4H-pyran-2-10carboxylic acid (0.13 g) was obtained. m.p. 236° C. (Compound 65 inTable 4).

EXAMPLE 10

[0168] a) To a solution of5-(4-chlorophenyl)-6-(4-15:methanesulfonylphenyl)-4-oxo-4H-pyran-2-carbaldehyde(0.74 g, 1.9 mmoles) in methylene chloride (10 ml), diethylaminosulfideDAST (0.61 g, 3.8 mmoles) was slowly added at 0° C. The reaction mixturewas stirred at this temperature for 1 hour and at room temperature for16 hours. The mixture was diluted with methylene chloride (10 ml). Theorganic phase was washed with water, dried (Na₂SO₄), and the solvent wasremoved under reduced pressure. The resulting residue was purified bycolumn chromatography with silica gel and ethyl acetate/n-hexane (1:1)as eluent; 3-(4-chlorophenyl)-6-difluoromethyl-2-(4-25methanesulfonylphenyl)pyran-4-one (0.1 g) was obtained. m.p. 168-170° C.(Compound 67 in Table 4).

[0169] The 2-phenylpyran-4-one derivatives of general formula (I)included in Table 4 were prepared according to the processes disclosedin these Examples, but with the appropriate starting materials. TABLE 4

Melting Com- Method Point pound R1 X R2 R3 Example (° C.) 1 CH₃ singleC₆H₅ CH₃ 1 185 bond 2 CH₃ single 4-FC₆H₄ CH₃ 1 237 bond 3 CH₃ single3-FC₆H₄ CH₃ 1 182 bond 4 CH₃ single 2-FC₆H₄ CH₃ 1 136-137 bond 5 CH₃single 4-ClC₆H₄ CH₃ 1 182 bond 6 CH₃ single 3-ClC₆H₄ CH₃ 1 131 bond 7CH₃ single 2-ClC₆H₄ CH₃ 1 148 bond 8 CH₃ single 4-BrC₆H₄ CH₃ 1 198 bond9 CH₃ single 3-BrC₆H₄ CH₃ 1 178 bond 10 CH₃ single 4-CH₃C₆H₄ CH₃ 1 205bond 11 CH₃ single 3-CH₃C₆H₄ CH₃ 1 126 bond 12 CH₃ single 2-CH₃C₆H₄ CH₃1 91-93 bond 13 CH₃ single 4-CF₃C₆H₄ CH₃ 1 172 bond 14 CH₃ single2,3-diFC₆H₃ CH₃ 1 187 bond 15 CH₃ single 2,4-diFC₆H₃ CH₃ 1 208 bond 16CH₃ single 3,4-diFC₆H₃ CH₃ 1 207 bond 17 CH₃ single 3,5-diFC₆H₃ CH₃ 1210 bond 18 CH₃ single 2,5-diFC₆H₃ CH₃ 1 183 bond 19 CH₃ single2,6-diFC₆H₃ CH₃ 1 206 bond 20 CH₃ single 2,3-diClC₆H₃ CH₃ 1 200 bond 21CH₃ single 2,4-diClC₆H₃ CH₃ 1 203 bond 22 CH₃ single 3,4-diClC₆H₃ CH₃ 1156 bond 23 CH₃ single 2,5-diClC₆H₃ CH₃ 1 230 bond 24 CH₃ single2,6-diClC₆H₃ CH₃ 1 186 bond 25 CH₃ single 6-F, 2-ClC₆H₃ CH₃ 1 177 bond26 CH₃ single 2-F, 4-ClC₆H₃ CH₃ 1 171 bond 27 CH₃ single 4-F, 2-ClC₆H₃CH₃ 1 113 bond 28 CH₃ single 4-Cl, 3- CH₃ 1 98-99 bond CH₃C₆H₃ 29 CH₃single 3-Cl, 4- CH₃ 1 176 bond CH₃C₆H₃ 30 CH₃ single 3-F, 4- CH₃ 1 137bond CH₃OC₆H₃ 31 CH₃ single 3-Cl, 4- CH₃ 1 116 bond CH₃OC₆H₃ 32 CH₃single i-C₃H₇ CH₃ 1 108 bond 33 CH₃ single C₆H₁₁ CH₃ 1 98-99 bond(cyclohexyl) 34 CH₃ single 2-naphthyl CH₃ 1 122-123 bond 35 CH₃ single2-indanyl CH₃ 1 169 bond 36 CH₃ single 2-tetra- CH₃ 1 103 bondhydronaphthyl 37 CH₃ CH₂ C₆H₅ CH₃ 1 137 38 CH₃ O C₆H₅ CH₃ 2 169 39 CH₃ O4-FC₆H₄ CH₃ 2 189 40 CH₃ O 2-FC₆H₄ CH₃ 2 178 41 CH₃ O 4-ClC₆H₄ CH₃ 2 19642 CH₃ O 2-ClC₆H₄ CH₃ 2 198 43 CH₃ O 4-BrC₆H₄ CH₃ 2 188 44 CH₃ O4-CH₃C₆H₄ CH₃ 2 183 45 CH₃ O 2,4-diFC₆H₃ CH₃ 2 191 46 CH₃ O 3,4-diFC₆H₃CH₃ 2 194 47 CH₃ O 2,5-diFC₆H₃ CH₃ 2 189 48 CH₃ O 2,6-diFC₆H₃ CH₃ 2 16949 CH₃ O 3,4-diClC₆H₃ CH₃ 2 177 50 CH₃ O 2,6-diClC₆H₃ CH₃ 2 170 51 CH₃ O4-Cl,3- CH₃ 2 183 CH₃C₆H₃ 52 CH₃ O 2,3,6- CH₃ 2 216 triClC₆H₂ 53 CH₃ O2,4,6- CH₃ 2 171 triClC₅H₂ 54 NH₂ single C₆H₅ CH₃ 3 218 bond 55 NH₂single 4-FC₆H₄ CH₃ 3 247 bond 56 NH₂ single 3,4-diClC₅H₃ CH₃ 4 128 bond57 NH₂ O 4-ClC₆H₄ CH₃ 5 221 58 CH₃ single 4-ClC₆H₄ CN 6 189 bond 59 CH₃single 2,4-diFC₆H₃ CN 6 113 bond 60 CH₃ single 4-ClC₆H₄ CH₂OH 7 120 bond61 CH₃ single 4-BrC₆H₄ CH₂OH 7 128-129 bond 62 CH₃ single 2,4-diFC₆H₃CH₂OH 7 173-175 bond 63 CH₃ single 4-ClC₆H₄ CH₂O- 8 162 bond CH₃ 64 CH₃single 2,4-diFC₆H₃ CH₂O- 8 184 bond CH₃ 65 CH₃ single 4-ClC₆H₄ COOH 9236 bond 66 CH₃ single 2,4-diFC₆H₃ COOH 9 241 bond 67 CH₃ single4-ClC_(6H) ₄ CF₂H 10 168-170

[0170] Examples 11 and 12 illustrate pharmaceutical compositionsaccording to the present invention and procedure for their preparation.Active ingredients 2.5 Kg Lactose monohydrate 5 Kg Colloidal siliconedioxide 0.05 Kg Corn starch 0.5 Kg Magnesium stearate 0.1 Kg

[0171] Procedure

[0172] The above ingredients were sieved through a 60 mesh sieve, andwere loaded into a suitable mixer and filled into 25,000 gelatinecapsules.

EXAMPLE 12

[0173] 100,000 Tablets each containing 50 mg of the3-(2,4-difluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one(active ingredient) were prepared from the following formulation: Activeingredient 5 Kg Spray dried lactose 19.9 Kg Microcrystalline cellulose3.9 Kg Sodium stearyl fumarate 0.2 Kg Colloidal silicon dioxide 0.2 KgCarboxymethyl starch 0.8 Kg

[0174] Procedure

[0175] All the powders were passed through a screen with an aperture of0.6 mm, then mixed in a suitable mixer for 20 ,minutes and compressedinto 300 mg tablets using 9 mm disc and flat bevelled punches. Thedisintegration time of the tablets was about 3 minutes.

1. A compound of formula (I):

wherein: R¹ represents an alkyl or —NR⁴R⁵ group, wherein R⁴ and R⁵ eachindependently represents a hydrogen atom or an alkyl group; R²represents an alkyl, C₃-C₇ cycloalkyl, pyridyl, thienyl, naphthyl,tetrahydronaphthyl or indanyl group, or a phenyl group which may beunsubstituted or substituted by one or more halogen atoms or alkyl,trifluoromethyl, hydroxy, alkoxy, methylthio, amino, mono- ordialkylamino, hydroxyalkyl or hydroxycarbonyl groups; R³ represents amethyl, hydroxymethyl, alkoxymethyl, C₃-C₇ cycloalkoxymethyl,benzyloxymethyl, hydroxycarbonyl, nitrile, trifluoromethyl ordifluoromethyl group or a CH₂—R⁶ group wherein R⁶ represents an alkylgroup; and X represents a single bond, an oxygen atom, a sulfur atom ora methylene group; or a pharmaceutically acceptable salt thereof.
 2. Acompound according to claim 1 wherein R¹ represents an unsubstitutedalkyl group or NR₂, R² represents a branched alkyl, C₃-C₇ cycloalkyl,naphthyl, tetrahydronaphthyl or indanyl group, an unsubstituted phenylgroup or a phenyl group substituted by one or more halogen atoms, alkylgroups and/or alkoxy groups, R³ represents an unsubstituted alkyl group,a nitrile group, a hydroxymethyl group, a methoxymethyl group, adifluoromethyl group or a hydroxycarbonyl group and X represents asingle bond, an oxygen atom or a methylene group.
 3. A compoundaccording to claim 1 or 2 wherein R¹ represents a methyl group, R²represents an unsubstituted phenyl group or a phenyl group substitutedby 1, 2 or 3 substituents independently selected from halogen atoms,methoxy groups and methyl groups and R³ represents a methyl group,methoxymethyl group or difluoromethyl group.
 4. A compound according toany one of claims 1 to 3 wherein R² represents a phenyl groupsubstituted by 1, 2 or 3 substituents independently selected fromhalogen atoms, methoxy groups and methyl groups, one of the substituentsbeing on the 4-position.
 5. A compound according to any one of claims 1to 3 wherein R² represents a phenyl group substituted by one or twohalogen atoms at least one of which is on the 4-position or the2-position. 6.3-(4-fluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran.-4-one,3-(2-fluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4 -one,3-(4-chlorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,3-(4-bromophenyl)-2-(4-methylsulfonylphenyl)-6-methylpyran-4-one,3-(2,4-difluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,3-3,4-dichlorophenyl)-2-(4-methanesulfonylphenyl )-6-methylpyran-4-one,3-(3-chloro-4-methylphenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,2-(4-methanesulfonylphenyl)-6-methyl-3-phenoxypyran-4-one, 2-(4-fluorophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,3-(2-fluorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one,3-(4-chlorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one,3-(2-chlorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one,3-(4-bromophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,2-(4-methanesulfonylphenyl)-6-methyl-3-(4-methylphenoxy)pyran-4-one,3-(2,4-difluorophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,3-(2,5-difluorophenoxy)-2-(methanesulfonylphenyl)-G-methylpyran-4-one,3-4-chlorophenyl)-2-(4-methanesulfonylphenyl)-6-methoxymethylpyran-4-one,3-(4-chlorophenyl)-6-difluoromethyl-2-(4-methanesulfonylphenyl) pyran-4-one, and pharmaceutically acceptable salts thereof.
 7. A process forthe preparation of a compound of formula (I) as defined in any one ofthe preceding claims which process comprises: (a) wherein R¹ is an alkylor —NR⁴R⁵ group in which R⁴ and R⁵ each independently is an alkyl group,R³ is a methyl group and R² and X are as defined in any one of claims 1to 5, reacting a carbonyl derivative of formula (III):

wherein R^(1a) is an alkyl or a —NR^(4a)R^(5a) group in which R^(4a) andR^(5a) are each independently alkyl groups and R² and X are as definedin any one of claims 1 to 5, with an excess of anhydrous acetic acid andpolyphosphoric acid at a temperature from 100° C. to 150° C.; (b)wherein R¹ is an alkyl group, R³ is a methyl group, X is as defined inany one of claims 1 to 5 with the proviso that it is other than a sulfura atom and R² is as defined in any one of claims 1 to 5, reacting amercapto derivative of formula (VIII)

wherein R^(1b) is an alkyl group, X^(b) is as defined for X in any oneof claims 1 to 5 with the proviso that it is other than a sulfur atomand R² is as defined in any one of claims 1 to 5, with an oxidizingagent; (c) wherein R¹ is a —NR⁶R⁵ group, R³ is a methyl group and R²,R⁴, R⁵ and X are as defined in any one of claims 1 to 5, reacting achlorosulfonyl derivative of formula (X):

wherein R² and X are as defined in any one of claims 1 to 5, with anamine of formula (XI): R⁴—NH—R⁵   (XI) wherein R⁴ and R⁵ are as definedin any one of claims 1 to 5, or (d) wherein R¹ is a NR⁴R⁵ group whereinR⁴ and R⁵ are hydrogen, R³ is a methyl group and R² and X are as definedin any one of claims 1 to 5, by debenzylation of the correspondingN,N-dibenzyl derivative of formula (XIV):

wherein R² and X are as defined in any one of claims 1 to
 5. 8. Use of acompound of formula (III):

wherein is an alkyl or —NR^(4a)R^(5a) group in which R^(4a) and R^(5a)are each independently alkyl groups, and R² and X are as defined in anyone of claims 1 to 5, in the preparation of a compound of formula (1) asdefined in any one of claims 1 to
 6. 9. Use according to claim 8 whereinR^(1a) is a methyl phenyl, 4-fluorophenyl, 2-fluorophenyl,4-chlorophenyl, 2-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl,2,6-difluorophenyl, 3,4-dichlorophenyl, 2,6-dichlorophenyl,4-chloro-3-methylphenyl, 2,3,6-trichlorophenyl and2,4,6-trichlorophenyl.
 10. Use of a compound of formula (VI):

wherein R^(1a) is an alkyl or —NR^(4a)R^(5a) group in which R^(4a) andR^(5a) are each independently alkyl groups, X^(b) is as defined for X inany one of claims I to 5 with the proviso that it is other than a sulfuratom and R² is as defined in any one of claims 1 to 5, in thepreparation of a compound of formula (I) as defined in any one of claims1 to
 6. 11. Use according to claim 10 wherein R^(1a) is a methyl group,X is an oxygen atom and R² is selected from phenyl, 4-fluorophenyl,2-fluorophenyl, 4-chlorophenyl, 2-chlorophenyl, 4-bromophenyl,4-methylphenyl, 2,4-difluorophenyl, 3,4-difluorophenyl,2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-dichlorophenyl,2,6-dichlorophenyl, 4-chloro-3-methylphenyl, 2,3,6-trichlorophenyl and2,4,6-trichlorophenyl.
 12. Use of a compound of formula (XVI):

wherein R² and R² are as defined in any one of claims 1 to 5, in thepreparation of a compound of formula (I) as defined in any one of claims1 to 5 wherein R³ is other than a methyl group.
 13. A pharmaceuticalcomposition comprising a compound according to any one of claims 1 to 6or pharmaceutically acceptable salt thereof in admixture with apharmaceutically acceptable carrier or diluent.
 14. A compound accordingto any one of claims 1 to 6 or a composition according to claim 13 foruse in a method of treatment of the human or animal body by therapy. 15.Use of a compound according to any one of claims 1 to 6 or a compositionaccording to claim 13 for the manufacture of a medicament for use in thetreatment of pain, fever or inflammation, to inhibit prostanoid-inducedsmooth muscle contraction or for the prevention of colorectal cancer orneurodegenerative diseases.
 16. A method for treating pain, fever orinflammation, inhibiting prostanoid-induced smooth muscle contraction orpreventing colorectal cancer or neurodegenerative diseases whichcomprises administering to a human or animal subject in need oftreatment an effective amount of a compound according to any one ofclaims 1 to 6 or a composition according to claim 13.